Gradient EH&S Nano News
A New US EPA Interpretation for Nanomaterials Could Affect New Pesticide Regulations under FIFRA
An April 29, 2010 presentation at the United States Environmental Protection Agency (US EPA) Pesticide Program Dialogue Committee by William Jordan, a Senior Policy Adviser with the US EPA Office of Pesticide Programs (OPP), describes a Federal Register Notice on nanomaterials and pesticide products that is expected to be issued in June 2010. The Federal Register Notice will propose a new policy requiring additional reporting pursuant to Section 6(a)(2) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). This section of FIFRA requires pesticide product registrants to submit adverse effects information about their products to US EPA. Jordan explained in his presentation that the basis for the decision to use the 6(a)(2) mechanism stems from the fact that "there are many studies that raise concerns that nanoscale materials may potentially affect human health and the environment adversely." Therefore, this proposed new requirement would place the burden of proving the safety and/or continued safety of the respective product on the registrant(s). Jordan explained that this would apply to already registered products as well as products pending registration. Products that have "an ingredient that contains particles that have been intentionally produced to have at least one dimension that measures between approximately 1 and 100 nanometers" would reportedly be subject to this new interpretation. This new interpretation would also apply when a non-nanoscale form of that same active or inert ingredient is already in a registered product (e.g., nanosilver, despite silver being listed as a registered pesticide).
For more information, and to download a copy of this presentation, visit: http://www.nanotechproject.org/
A draft agenda of the US EPA Pesticide Program Dialogue Committee meeting is available here: http://www.epa.gov/
Third Report to the President and Congress on the Assessment of the National Nanotechnology Initiative is Submitted
On March 12, 2010, the "Report to the President and Congress on the Third Assessment of the National Nanotechnology Initiative (NNI)" was released by the President’s Council of Advisors on Science and Technology (PCAST). This report presents the opinion of a working group of three PCAST members, and 12 non-governmental members, on the status of the NNI. The group addressed four main areas: NNI program management; the development ("outputs") of nanotechnology; environment, health, and safety (EHS) research; and the vision for NNI over the next ten years. With respect to EHS research, the working group assessed the ability of NNI to orchestrate the identification and management of potential risks associated with nanotechnology, and follow through on recommendations made during the 2008 review of NNI. The working group noted that significant EHS-related barriers to the effective, sustainable, and responsible commercialization of nanotechnology still existed. The working group recommended that member agencies increase coordinated efforts to overcome these barriers. To facilitate this, the working group recommended a stronger focus over the next 10 years on fundamental issues related to EHS, coordinated by the National Institutes of Health (NIH), National Institute of Standards and Technology (NIST), United States Environmental Protection Agency (US EPA), and other relevant agencies.
For more information, and to download a copy of the report, visit: http://www.whitehouse.gov/
New OECD Document Describes the Status of Regulatory Regimes for Manufactured Nanomaterials
A recent Organisation for Economic Co-operation and Development (OECD) report describes how member countries (e.g., European Union, Japan, New Zealand, Sweden, Australia, United States, and United Kingdom) address information requirements, hazard identification, exposure mitigation, risk assessment, and risk management measures for manufactured nanomaterials. The data described in the report were collected from a questionnaire distributed in July 2008 on regulatory information of manufactured nanomaterials. In total, 24 responses were received from nine jurisdictions covering a wide variety of materials (e.g., industrial chemicals, pesticides, fertilizers, agricultural compounds, fuels and fuel additives, food and food additives, and veterinary medicines). The legislation described in the report pertained to issues such as occupational health and safety, consumer product safety, the control of major accidents, and packaging requirements. OECD cautions readers that specific features of the report may not be relevant for all legislative mandates, nanomaterials, or products, as the reported data are not representative of all industries. Despite the lack of specific regulations in many jurisdictions, OECD found that nanomaterials may be subject to existing legislation. It also noted that while key features of various regulations have been summarized, their effectiveness in allowing risk assessors to protect the environment and human health, as it relates to nanomaterials, has not been determined.
For more information, or to view this report, visit: http://www.olis.oecd.org/ Reports, Reviews, White Papers, and Books
Human Health Risk Assessment Data on Engineered Nanomaterials (ENMs) Are Lacking
Savolainen, K; Alenius, H; Norppa, H; Pylkkanen, L; Tuomi, T; Kasper, G.
A review by Kai Savolainen and colleagues at the Finnish Institute of Occupational Health suggests that the potential for occupational exposure to engineered nanomaterials (ENMs) is likely to significantly increase, yet our current ability to quantify the human health risk is insufficient. The authors suggest that the features of ENMs that make them technologically desirable (e.g., small size, high surface to mass ratio, and surface reactivity) also present the greatest unknown human health risk. Savolainen et al. (2010) address how an ad hoc risk assessment of all ENMs under the existing hazard identification framework would be an immense task, as there are currently about 50,000 different types of carbon nanotubes due to different raw materials, production processes, and catalysts. Savolainen et al. (2010) suggest that this has resulted in a lack of quality data on both exposure and toxicity. The authors argue for new testing strategies to capture more relevant data and to address key data gaps in ENM aerosol standards and appropriate metrics; cost-effective and dependable exposure data; and biological data on translocation and toxicity, as well as testing strategies relevant to the exposure scenarios.
For more information, or to view the abstract of this paper, visit: http://www.ncbi.nlm.nih.gov/ Hot-off-the-Presses: Peer-Reviewed Research Articles of Note
Sadrieh, N; Wokovich, AM; Gopee, NV; Zheng, J; Haines, D; Parmiter, D; Siitonen, PH; Cozart, CR; Patri, AK; McNeil, SE; Howard, PC; Doub, WH; Buhse, LF. 2010. "Lack of Significant Dermal Penetration of Titanium Dioxide (TiO2) from Sunscreen Formulations containing Nano- and Sub-Micron-Size TiO2 Particles." Toxicological Sciences (Advance Manuscript 2/15/2010).
Synopsis:
- Titanium dioxide (TiO2) is widely used in sunscreen products to reduce the penetration of ultraviolet (UV) light. In an effort to decrease the opacity of sunscreens, manufacturers are decreasing the size of TiO2 particles (from micron to sub-micron or nano-size), thereby increasing the surface area and light reflecting and blocking properties. Nano-sized particles continue to reflect or block shorter wavelength UV light (280-400 nm), while passing visible light. The potential for absorption of nanoparticles through the skin has raised some public health concerns. Using minipigs, which are considered to provide a useful tool for assessing dermal absorption, this study directly addressed the question of whether nano and sub-micron-size TiO2 nanoparticles could penetrate the skin and be distributed throughout the body.
- Sadrieh et al. (2010) conducted a dermal penetration study using minipigs (female Yucatan minipigs approximately four months of age) exposed to four sunscreens at 2 mg cream/cm2 skin (four applications/day, five days/week, for four weeks). The four sunscreens contained either 0.334 mg Ti/g (control-blank cream), 33.7 mg Ti/g (300-500 nm TiO2), 36.6 mg Ti/g (30-50 nm uncoated TiO2), or 28.5 mg Ti/g [20-30 nm coated (aluminum hydroxide/dimethicone copolymer) TiO2 about 50-150 nm in length]. The sunscreens were applied uniformly over the neck and dorsal surface and the ventral abdomen ending at the base of the tail. After the four-week application, skin, lymph nodes, liver, spleen, and kidneys were removed and analyzed for TiO2 content [by inductively coupled plasma-mass spectrometry (ICP-MS)].
- Skin samples were also subjected to transmission electron microscope (TEM) and scanning electron microscope-energy dispersive X-ray (SEM-EDX) analysis. These examinations were used to evaluate the localization of particles within the dermis (i.e., inner layer of skin below the outer epidermis) of treated animals. Skin sections of the epidermis (i.e., outer layer of skin), interfollicular areas (i.e., areas between hair follicles), and follicular lumens (i.e., area around the follicle cavity) were examined for particle distribution.
- None of the sunscreen applications were found to be irritating to the animal skin. Significantly increased levels of titanium were found in the epidermis and dermis of treated animals compared to controls. Titanium levels in the epidermis from control, sub-micron, uncoated nano-sized, and coated nano-sized TiO2 were 0.035, 2.11, 2.57, and 5.05 mg/g tissue, respectively, whereas the levels in the dermis were 1.003, 7.34, 5.17, and 10.92 μg/g. The results demonstrate that the amount of titanium found in the epidermis was 35-, 287-, 498-, and 463-fold higher than the levels in the dermis.
- Titanium levels in lymph nodes and livers were not significantly different from controls. Analysis of the particle distribution in the epidermis and dermis showed no significant penetration. Nanoparticles from all three sunscreen formulations were found in the stratum corneum and no pattern of distribution was observed (i.e., there was no uniform decrease in the number of particles from epidermis to dermis). Few particles (< 50 or < 0.001% of the applied dose) were estimated, using TEM and SEM-EDX analysis, in the lower epidermis layer, and the authors suggested this may have been due to cross-contamination during the tissue sectioning. The findings suggest that there is no significant absorption or penetration of the TiO2 nanoparticles examined.
Discussion and Implications:
- The work conducted by Sadrieh et al. (2010) provides some evidence that nano-sized TiO2 in sunscreens is unlikely to significantly penetrate healthy human skin. Further, the results suggest that the dermis and other organs may not be at risk from accumulating nano-sized TiO2. The authors used concentrations of TiO2 that are relevant to concentrations used in publically available sunscreens and an animal model that has direct relevance to humans (i.e., similar in epidermal cellular thickness, physiology, and hair follicle density).
- All three TiO2 particles tested were found in the stratum corneum and upper follicular lumens. The authors noted that coated nano-sized TiO2 particles were found in higher concentrations than uncoated sub-micron or nano-sized particles; however, this did not reflect a difference in total amount of TiO2 in the skin or a significant difference in titanium in other tissues. Further examination of TiO2 particles and coatings is warranted to clarify which combinations yield the greatest UV protection with minimal potential for absorption.
- The authors also noted that these results do not describe TiO2 penetration for other conditions (e.g., applied to damaged or unhealthy skin). In addition, the study was conducted under controlled conditions, while typical application of sunscreens occurs in combination with elevated temperatures, UV light, and physical activity. Therefore, additional factors should be considered before a final safety determination is completed.
Current NIOSH Research Efforts Discussed at AIHA Meeting
Tom Lewandowski, Ph.D., DABT, ERT
On May 27, 2010, National Institute for Occupational Safety and Health (NIOSH) scientists gave a presentation at the annual American Industrial Hygiene Association (AIHA) conference relating to recent NIOSH research activities concerning nanomaterials. Dr. Charles Geraci, coordinator of the NIOSH Nanotechnology Research Center, noted that NIOSH is currently developing risk management guidance for nanomaterials that includes medical surveillance recommendations. The guidance is currently undergoing internal review and will be released later this summer for public and stakeholder comment. Geraci noted that the agency is also working on developing rapid screening techniques for predicting bioactivity of nanomaterials.
Geraci summarized recent NIOSH findings in the area of nanotoxicology. He focused on three primary materials:
- Concerning single-walled carbon nanotubes (SWCNT), he reported that short-term animal studies involving repeated exposures of up to two hours have demonstrated transient inflammation and fibrosis as well as oxidant stress in aortic and coronary tissue (the species and route of administration were not specified). NIOSH has also observed evidence of increased atherosclerosis in mice administered SWCNT via tracheal instillation.
- Concerning titanium dioxide (TiO2) nanoparticles, Geraci indicated that short-term exposures in rats have resulted in transient pulmonary inflammation (dosing was apparently via intraperitoneal injection, based on review of recent publications involving NIOSH scientists). NIOSH researchers also detected inflammatory signals in certain areas of the brain. Geraci noted that this does not indicate toxicity per se but is suggestive of "something going on." Studies of TiO2 nanoparticles administered via inhalation to rats have also shown dysfunction of systemic and coronary blood microvasculature, specifically a failure of the vessels to dilate properly.
- Concerning multi-walled carbon nanotubes (MWCNT), Geraci summarized short-term exposure studies in mice (with dosing via aspiration), which have also shown transient pulmonary inflammation as well as rapid and persistent fibrosis. Similar to its findings with titanium dioxide, Geraci indicated that NIOSH has also observed inflammation and damage markers in certain areas of the brain in these studies (the results are summarized on the NIOSH science blog – http://www.cdc.gov/niosh/blog/nsb031909_mwcnt.html). The researchers have also found that MWCNT can migrate from the outer surface of the alveolar space into the intrapleural space. Geraci noted that this indicates that MWCNT behave like asbestos in terms of migration but any similarity in terms of potential for cancer induction is not yet known.
Geraci also discussed NIOSH plans for an industry-wide exposure assessment and epidemiology study. As part of the effort, 139 companies producing nanomaterials were identified and 61 were considered eligible for further evaluation. Of these, 21 companies agreed to participate. Geraci noted that of the facilities identified, 73% make carbon nanotubes (CNT) and many are small facilities or subunits of larger companies. NIOSH will start facility sampling in late 2010. The agency is also considering a companion biomarker collection program (specific biomarkers not yet determined).
The initial questionnaire requested that companies provide information concerning workplace practices. The results indicate that the most common control in these facilities was use of a chemical fume hood. Most facilities indicated they provided employees with personal protective equipment (PPE); in most cases this consisted of gloves and aprons. Seventy-six percent of facilities indicated they provide employees with some kind of respiratory protection when working directly with nanomaterials.
Geraci's talk was followed by a presentation by researcher Dr. Mark Methner, who discussed some of NIOSH's findings from 26 site visits already conducted. Of particular note was the observation that conducting processes in chemical fume hoods did not completely prevent entrainment of nanoparticles into room air. However, the amount of material escaping was not quantified. Methner also noted that CNT prepared as aqueous solutions for use in dosing of animals could produce an aerosol when the solution was sonicated. When the aerosol droplets dried, the nanofibers could then be entrained into room air. Methner concluded by calling for exposure limits for nanomaterials. However, there was no discussion as to the basis for such exposure limits – e.g., particle count versus particle basis, nor how differences in toxicity among different CNTs would be addressed.
A subsequent presentation by NIOSH scientist Dr. Ron Shaffer described work related to NIOSH's nanomaterial respiratory protection program. A key point was that typical respirator particulate filters (e.g., p95, p100, CE FFP2, FFP3) are very effective at capturing nano-sized particles. Normal dust and surgical masks were found to not be very effective. NIOSH studies also showed that nanoparticles are not more likely than normal sized particles to penetrate leaks around respirator face seals. They also showed no increased tendency to penetrate fabric swatches from materials typically used for lab coats. Shaffer noted that most of the studies conducted to date in this area of research have been done with spherical particles and similar work is required for CNT to determine if these materials behave comparably.
Guest ContributorThe Definitional Conundrum in Nanotechnology Regulation
Gary E. Marchant, Ph.D., J.D. Arizona State University College of Law
Government agencies around the world are actively developing regulations for nanoscale materials that in many cases are scheduled to be proposed later this year. For example, the United States Environmental Protection Agency (US EPA) is reportedly working on a Section 4 test rule, a Section 8(a) reporting rule, and a comprehensive Significant New Use Rule (SNUR) for nanomaterials, all under the Toxic Substances Control Act, for proposal later this year. US EPA’s Office of Pesticide Programs is preparing to propose a new policy for nanoscale materials that are present as active or inert ingredients in pesticides. The European Union is preparing to require labeling for nanomaterials in cosmetics and foods.
These and other pending regulatory actions for nanotechnology are likely to be frustrated by the absence of a scientifically valid and legally enforceable definition of nanotechnology. A number of different and inconsistent definitions of nanotechnology have been suggested. Many definitions specify a size range of 1-100 nm, although some increase the upper limit to 200 or 300 nm, while some others omit a lower limit. Some definitions refer to sizes in one dimension, others in two dimensions, and still others in three. Some require a size specification plus some (unspecified) special property, some specify size but not special properties, and still others require special properties but specify no size range. In short, there are many disparate definitions but no consensus on how nanotechnology should be defined.
The biggest problem is not, however, that there are too many definitions, but rather that there is no definition offered to date that is scientifically credible and legally plausible. Nanotechnology encompasses a very broad range of materials, products and applications that involve unique properties at small sizes. But there is no magical size cut-off that applies across all these various types of nanotechnology. Thus, it makes no scientific sense to say that a particle of a given type is nanotechnology if it is 95 nm in diameter but not if it is 105 nm. Indeed, the relevant size range when nano-specific properties exist likely differs across different nanomaterials. Another complication is that any product or material is almost certain to include some particles in the 1-100 nm size range. So when is something nano? When more than half of the material is in the specified size range? When 100% is? 10%? 1%? And if we set such an arbitrary limit, won’t it cause enormous confusion and compliance problems when batches of material differ based on process variations or strategic behavior?
A legally enforceable regulation that covers all nanomaterials will need to provide a definition that provides a bright-line rule that clearly differentiates nano from non-nano materials. Such a definition does not currently exist. Accordingly, any attempt to regulate nanotechnology as a whole is doomed to failure. Instead, regulators may want to focus on specific, more easily defined nanomaterials, or update regulatory regimes so that they adequately regulate all materials, whether they be nano or not.